The film's basic plot was conceived in 1994, when Robert Rodriguez was working on Desperado. He presented a draft of the script to 20th Century Fox, but they turned it down because the budget required was too large. 15 years later, the studio decided to follow through with his script; in the end, an updated version of his script.
The original script contained cameo appearances by Dutch (Arnold Schwarzenegger) and Michael Harrigan (Danny Glover), the protagonists of the previous Predator films. However, these appearances were ultimately cut out.
Nimród Antal specifically chose Adrien Brody for the main protagonist: "It was a challenge in finding a balance. When we cast Adrien, there were a lot of people going, What? But at the same time, if we cast a Vin Diesel in that role or anyone who is Arnold-esque, we would have been attacked for doing that. So we decided early on to go in a very different direction as far as the casting process, but it turned out fantastic." He also felt the soldiers should be portrayed as wiry tough guys, not burly men like Arnold Schwarzenegger.
According to Robert Rodriguez, the title of "Predators" serves as a double-entendre, describing the alien hunters as well as the ensemble human characters they target: "They could very well kill each other off even if there were no Predators!"
Nikolai was originally supposed to be armed with a Russian GShG-7.62 four-barreled rotary machinegun, as it would be more fitting for a Russian spetsnaz operator. The production crew was unable to obtain one, so they used an American M134 minigun instead.
Isabelle uses a Blaser R93 sniper rifle fitted with an Elcan DigitalHunter scope. The official sniper rifle for active-duty Israeli Defense Forces personnel is actually the H-S Precision HTR, and it achieved that designation in May 2010, only a month before this movie was released.
Hanzo's name is a reference to Hattori Hanzo, a legendary Japanese samurai of the Sengoku era (1467-1573 AD). Hattori Hanzo is also the name of Sonny Chiba's character in Kill Bill: Vol. 1, which was written and directed by Robert Rodriguez's good friend Quentin Tarantino.
Stans' character is a death row inmate in California's San Quentin Correctional Facility. All death row inmates can receive a pardon or stay of execution by the state's governor. At the time this film was made (and presumably the time the movie takes place), California's governor was Arnold Schwarzenegger, the lead star of the original Predator film.
The plant that Edwin (Topher Grace) identifies as "Archaefructus liaoningensis" has actually been extinct for several million years; its origin lies in the Cretaceous Period. Angiosperm fossils were found in China that are believed to be about 125 million years old, making it the world's earliest known flowering plant. In an earlier draft of the script, Edwin highlights the plant's origins, citing it as yet another inexplicable oddity before they finally realize where they are.
According to Nimród Antal and Robert Rodriguez on the commentary, in the script, the character Cuchillo was described as "a guy who looks like Danny Trejo." When Danny Trejo heard this, he called Robert Rodriguez and said, "hey, I heard there's a guy in the script for 'Predators' who looks just like Danny Trejo and guess what, I look just like Danny Trejo!"
Even though this installment in the "Predator" franchise explicitly wanted to part with the crossover AvP story arc, it does contain at least three nods to the "Alien" franchise: - 1) at one point, while (obviously, given the movie's universe) facing near-certain death, one character tells another "If the time comes, I'll do us both", a reference to Hicks' almost identical line in Aliens, 2) when the group finds the body of an earlier victim of the antagonists, he has a large hole in his chest with the ribs bent outwards, referencing the way xenomorph young emerge from their host and the wound found on the "space jockey" in Alien, 3) as soon as Royce recovers from his parachute landing; as he looks around a music motif from Aliens can be heard and when the group enters the Predators camp there's a brief view of an Alien skull on the ground.
According to Robert Rodriguez on the DVD commentary, Walton Goggins had been cast in the role of Stans, but Rodriguez felt the character was written far too much like the character Hudson in Aliens. So Rodriguez had the part re-written and asked director Nimród Antal to re-cast the role. But Antal insisted that Goggins could still do the role and scheduled a meeting between Goggins, Rodriguez and himself. Within a very short period of time, Rodriguez was convinced that Walton was still right for the part.
Hanzo is missing two fingers on his left hand. The reason that the Yakuza traditionally cut their fingers starting from the left pinkie is that these fingers have a vital role in controlling a Japanese sword, and their loss would significantly impair a duelist. Hanzo must be a formidable swordsman to be able fight in close combat as he did despite the loss of his fingers.